Project Summary This proposal is focused on the application of new mechanistic insights in non-covalent catalysis to the discovery of synthetically useful carbon-carbon bond-forming reactions. We outline entirely new approaches to catalysis of pericyclic reactions of anionic intermediates, to activation and stereocontrolled substitution reactions of acetals including C-glycosylation reactions, and to the construction of quaternary stereocenters from tertiary alcohols. In each aim, the proposed reaction manifolds are based on a firm mechanistic foundation gleaned from extensive preliminary investigations. In our studies of pericyclic reactions, we explore whether the stereoselectivity of reactions of prochiral anionic intermediates may be controlled using the principles of ion-pairing catalysis. To accomplish this aim we will design polyfunctional H-bond donor catalysts capable of dual anion- and cation-binding to activate the intermediate alkali metal-enolate and/or alkoxide ion pairs and to facilitate enantioinduction in their subsequent rearrangements. This principle will be applied to the development of catalytic asymmetric methods for the ester-enolate Ireland?Claisen and anionic oxy-Cope rearrangements. In a second aim, we seek to develop new methodologies for the generation of and subsequent stereocontrolled additions to oxocarbenium ions generated from stable acetal precursors utilizing hydrogen-bond donor catalysts in conjunction with trialkylsilyl triflate promoters. We have discovered that chiral squaramide catalysts activate silyl triflates to generate a complex wherein the amide N?H bonds participate in triflate binding and one of the squaramide carbonyls coordinates the silylium cation; this charge- separated intermediate displays remarkably heightened Lewis acidity relative to silyl triflates alone. We will apply this insight to enantioselective C-C bond-forming substitutions of acetals and catalyst-controlled diastereoselective C-glycosylation reactions. In a third aim, we apply the principles of anion-binding catalysis to stereoselective construction of quaternary centers via the generation and controlled trapping of tertiary carbocations. Based on extensive quantitative studies of anion abstraction, we have identified new classes of H-bond donor catalysts capable of generating unstabilized tertiary carbocations and of allowing their selective capture by weakly nucleophilic ?-C-centered nucleophiles. This reactivity principle will be developed in the context of steroselective alkylations of benzylic and allylic tertiary cations, and to cationic cyclization reactions analogous to those promoted by terpene cyclases. The direct output of the work described in this proposal will be valuable new carbon-carbon bond-forming reactions promoted by small-molecule, chiral catalysts that engage highly reactive ionic intermediates through networks of non-covalent interactions. More broadly, this work will provide a foundation for future applications of biomimetic strategies in catalyst design.